Cancer Etiology: A Metabolic Disease Originating from Life's Major Evolutionary Transition?

Abstract

A clear understanding of the origins of cancer is the basis of successful strategies for effective cancer prevention and management. The origin of cancer at the molecular and cellular levels is not well understood. Is the primary cause of the origin of cancer the genomic instability or impaired energy metabolism? An attempt was made to present cancer etiology originating from life's major evolutionary transition. The first evolutionary transition went from simple to complex cells when eukaryotic cells with glycolytic energy production merged with the oxidative mitochondrion (The Endosymbiosis Theory first proposed by Lynn Margulis in the 1960s). The second transition went from single-celled to multicellular organisms once the cells obtained mitochondria, which enabled them to obtain a higher amount of energy. Evidence will be presented that these two transitions, as well as the decline of NAD+ and ATP levels, are the root of cancer diseases. Restoring redox homeostasis and reactivation of mitochondrial oxidative metabolism are important factors in cancer prevention.

Figure 1

O₂ and NAD+ as limiting factors in driving oxidative phosphorylation. The figure presents a hypothesis that in situations with limited availability of NAD+, the cells will activate the program which switches off Krebs cycle and electron transport chain (process consumes 6 NAD+) and favors glycolysis (process consumes 2 NAD+) in order to obtain energy, preserve NAD+, and avoid cell death through reduced ATP production and activation of apoptosis. ^∗Abbreviations: PARP: poly(adenosine diphosphate [ADP] ribose) polymerases; CD38: NAD+ glycohydrolases; sirtuins: NAD-dependent histone deacetylase (“HDAC”) enzymes.

Figure 2

Metabolic alterations produce genetic alterations (activation of oncogenes and repression of tumor suppressor genes) which influence cancer development. What the causes are of metabolic alteration is still a matter of debate. Potential candidates involved in the metabolic switch from respiration to fermentation are increased inflammation, increased ROS formation, overstimulation of PARPs, decreased intracellular energy levels, and damaged respiration.